Department of Laboratory Medicine, Hallym University College of Medicine, Anyang-si, Korea.
Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea.
Xenotransplantation. 2017 May;24(3). doi: 10.1111/xen.12299. Epub 2017 Apr 18.
Several immunosuppression (IS) regimens achieve long-term graft survival in non-human primates (NHPs) after porcine islet transplantation (PITx), but their success rates vary. To understand the mechanism of graft loss, we investigated the relationships between graft survival and humoral or inflammatory responses for maintenance IS in NHPs after PITx.
Islets purified from adult wild-type pigs were intraportally transplanted into streptozotocin-induced diabetic rhesus monkeys. Three monkeys received an IS regimen without anti-CD154 monoclonal antibody (mAb, transplant [Tpl]-control) and 11 received IS with anti-CD154 mAb (Tpl-aCD154). Blood samples were obtained weekly from the recipients until graft function ceased and weekly from three healthy monkeys (non-Tpl-control) for 6 months. Levels of D-dimer, C-reactive protein (CRP), and anti-Galα1,3Gal (Gal) IgG, IgG1, IgG2, and IgM were measured. Liver biopsy sections were immunostained for fibrin, insulin, and human CD31.
Tpl-control monkeys had higher time-weighted average levels (levels ) of Δanti-Gal IgG (Δ, difference from level at day 0) and D-dimer than Tpl-aCD154 or non-Tpl-control. The levels of Δanti-Gal IgG, IgG1, IgG2, and IgM did not differ between Tpl-aCD154 and non-Tpl-control. The levels of D-dimer and Δanti-Gal IgG2 negatively correlated with graft survival. Liver biopsy sections revealed many spots of fibrin deposition inside islet grafts that were well vascularized by human CD31-positive cells. Level of D-dimer positively correlated with Δanti-Gal IgG1 in Tpl-control and with Δanti-Gal IgG2 in Tpl-aCD154.
Intravascular coagulation, in association with immune responses against xenografts, may partly contribute to loss of islet grafts in NHPs after PITx.
几种免疫抑制（IS）方案可在非人类灵长类动物（NHP）进行猪胰岛移植（PITx）后实现长期移植物存活，但成功率不同。为了了解移植物丢失的机制，我们研究了 PITx 后维持 NHP 中胰岛移植的 IS 中体液或炎症反应与移植物存活之间的关系。
从成年野生型猪中纯化的胰岛通过门静脉内移植到链脲佐菌素诱导的糖尿病恒河猴中。三只猴子接受无抗 CD154 单克隆抗体（mAb，移植[Tpl]-对照）的 IS 方案，11 只猴子接受有抗 CD154 mAb 的 IS 方案（Tpl-aCD154）。在移植物功能丧失之前，每周从受者获得血液样本，在 6 个月内每周从 3 只健康猴子（非 Tpl-对照）获得血液样本。测量 D-二聚体、C 反应蛋白（CRP）和抗 Galα1,3Gal（Gal）IgG、IgG1、IgG2 和 IgM 水平。免疫染色肝活检切片用于纤维蛋白、胰岛素和人 CD31。
Tpl-control 猴子的时间加权平均水平（水平）的 Δ抗 Gal IgG（Δ，与第 0 天的水平差异）和 D-二聚体比 Tpl-aCD154 或非 Tpl-control 高。Tpl-aCD154 和非 Tpl-control 之间的 Δ抗 Gal IgG、IgG1、IgG2 和 IgM 水平没有差异。D-二聚体和 Δ抗 Gal IgG2 水平与移植物存活呈负相关。肝活检切片显示在胰岛移植物内有许多纤维蛋白沉积点，这些点由人 CD31 阳性细胞很好地血管化。D-二聚体水平与 Tpl-control 中的 Δ抗 Gal IgG1 和 Tpl-aCD154 中的 Δ抗 Gal IgG2 呈正相关。
血管内凝血与针对异种移植物的免疫反应有关，可能部分导致 PITx 后 NHP 胰岛移植物丢失。
